Plasma Biomarkers in Amyotrophic Lateral Sclerosis
Abstract
Applicability of the research: For people with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig s disease, neurons in the brain (upper motor neurons or UMN) and the spinal cord (lower motor neurons or LMN) progressively degenerate, causing weakness of the muscles and a loss of function. The biology and symptoms of ALS, as well as how quickly the disease progresses, differ from individual to individual. Moreover, there is overlap with related disorders like primary lateral sclerosis, progressive muscular atrophy, and frontotemporal dementia. This diversity in the cause and manifestation of ALS is a major hurdle in the search for a cure and disease-modifying treatments: It can be difficult to disentangle a person s natural disease course from treatment effects. Biomarkers can provide important insights into an individual s disease for clinicians and researchers by helping to define biological subtypes of ALS and to predict long-term clinical outcomes. Recent technological advancements have made blood-based biomarkers, including plasma, accurate and reliable. Foremost among these blood-based biomarkers in ALS is neurofilament light chain (NfL). NfL levels increase in the plasma even at very early stages of the disease, up to a year before clinical symptoms appear, and have proven useful for predicting when clinically manifest disease will emerge. Here, we propose to investigate a new blood-biomarker of ALS: plasma phosphorylated tau 181 (p-tau181). While much research has proven the utility of plasma p-tau181 in another neurodegenerative disease, Alzheimer s disease, we find new and robust evidence that plasma p-tau181 is increased with LMN dysfunction in ALS. In this proposal, we evaluate and validate the utility of plasma p- tau181 in ALS. We test performance of plasma p-tau181, both alone and in combination with plasma NfL. We hypothesize that these two plasma biomarkers used in combination may boost our ability to differentiate between different subtypes of ALS and to predict long-term clinical outcomes. We test these hypotheses in three specific aims: (1) Classify clinical subtypes of ALS and related disorders using plasma p-tau181 and NfL. (2) Track how plasma p-tau181 changes with time, and test use of p-tau181 and NfL to predict ALS outcomes. (3) Evaluate p-tau181 as an early biomarker in individuals at risk for ALS, who do not yet show symptoms. What types of ALS patients will it help and how will it help them? Plasma p-tau181 is associated with LMN dysfunction and degeneration in ALS. Plasma p-tau181 may be used to track or predict spread of LMN symptoms, and to differentiate ALS and related disorders that have LMN predominant disease. In addition, there is some evidence that plasma p-tau181 is especially elevated in the genetic form of ALS due to a SOD1 point mutation. What are the potential clinical applications, benefits, and risks? We propose to test plasma p-tau181 in combination with plasma NfL. These two biomarkers are sensitive to distinct aspects of ALS disease processes: While plasma p-tau181 is associated with LMN disease, NfL indicates overall disease severity and is associated with UMN disease and bulbar signs. This means p-tau181 and NfL may provide different but complimentary information about ALS, and that their combination may have potential clinical application to better characterize the spectrum of ALS and related disorders. Benefits of plasma-based biomarkers include that they are relatively less expensive and less invasive than other biomarker modalities, and that new automated and ultra-sensitive assays have made quantification reliable. Moreover, blood draw can be completed at clinic or via at-home visits, enabling ease of longitudinal monitoring. Risks associated with blood-draw are minimal, most commonly pain or bruising at the site of needle injection. What is the projected time it may take to achieve a patient-related outcome? Clinical biomarkers
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310137
Entities
People
- Katheryn Cousins
Organizations
- United States Army
- University of Pennsylvania